Vascular integrin alpha(v)beta3: a new prognostic indicator in breast cancer

Blood vessel density is a prognostic indicator of multiple tumor types. Recently, it has been established that tumor-associated blood vessels express elevated levels of integrin alpha(v)beta3. In fact, there is evidence that integrin alpha(v)beta3 identifies the most proliferative endothelial cells within human breast carcinomas. Therefore, we evaluated breast cancer tissue in terms of both blood vessel density and alpha(v)beta3 expression. We found that the antibody LM609 to integrin alpha(v)beta3 preferentially stains the blood vessels of small caliber. Furthermore, comparative studies between LM609 and anti-CD31 antibodies on normal breast indicate that very low and weak expression of integrin alpha(v)beta3 was found on vessels within normal tissue, whereas CD31 antigen was expressed in almost all vasculature. Indeed, expression of integrin alpha(v)beta3 was significantly higher in tumors of patients with metastasis than in those without metastasis. In a series of 197 consecutive patients with invasive breast cancer and long follow-up, vascular expression of integrin alpha(v)beta3 in tumor vascular "hot spots" was found to be the most significant prognostic factor predictive of relapse-free survival in both node-negative and node-positive patients. These findings support the contention that angiogenesis plays a critical role in breast cancer progression and suggest that integrin alpha(v)beta3 is an endothelial cell marker with significant prognostic value and potential usefulness as a target for specific antiangiogenic therapy.     

Gene cloning, biochemical characterization and physiological role of a thermostable low-specificity L-threonine aldolase from Escherichia coli

BACKGROUND: This study was designed to determine the prognostic value of positive surgical resection margin or highest nodal station sampled at thoracotomy in patients with non-small cell lung cancer. METHODS: Two reviewers independently examined the surgical records and pathologic reports from a randomized trial comparing computed tomography versus mediastinoscopy for staging of lung cancer. They recorded pathologic findings at the surgical resection margin, the highest mediastinal nodal station sampled at thoracotomy, histologic type, tumor size, N status, and evidence of vascular or lymphatic invasion. These variables formed the independent variables in logistic regression models to predict recurrence. RESULTS: Except for 1 patient, follow-up at 3 years for 399 included patients was complete. Significant predictors of recurrence were tumor size (odds ratio [OR], 1.2 (per centimeter); 99% CI [confidence interval], 1.1 to 1.4), and N status (compared with N0, N1: OR, 1.6; CI, 0.8 to 3.1; N2: OR, 3.2; CI, 1.4 to 7.5). Other variables, including positive surgical resection margin, did not predict early recurrence or death. CONCLUSIONS: In patients with non-small cell lung cancer, surgical resection margin or highest nodal station sampled at thoracotomy that are involved by carcinoma do not predict recurrence. The current definition of incomplete resection has limited prognostic significance.     

Incidence of epilepsy in rural central Ethiopia

BACKGROUND: The value of these prognostic factors was compared with that of other clinicopathologic factors such as tumor grade, tumor stage, mucin production, vascular invasion, perineural invasion, and lymphatic invasion. OBJECTIVE: To determine whether the development of distant recurrence in patients with node-negative colon cancer could be predicted using vessel count and vascular endothelial growth factor (VEGF) expression. DESIGN: Paraffin-embedded colon cancers were immunostained for factor VIII, VEGF, basic fibroblast growth factor, and proliferating cell nuclear antigen; slides were reviewed for differentiation, mucin production, and the presence of vascular, lymphatic, and/or perineural invasion. SETTING: A large academic cancer referral center where 27 patients with node-negative colon cancer were operated on during 1988 and 1989. MAIN OUTCOME MEASURE: The development of and interval to recurrence. RESULTS: Eight patients developed liver, lung, or lymph node metastases at a median of 24 months. The median follow-up for patients without cancer recurrence was 60 months. The mean tumor vessel count for those patients who remained disease-free was significantly fewer than for those patients who suffered a recurrence (20 vs 33, respectively). By univariate analysis, 3 factors- perineural invasion, vessel count, and VEGF expression- were correlated with time to recurrence. By multivariate analysis, only vessel count was significantly related to differences in time to recurrence. Expression of VEGF correlated with vessel count. CONCLUSION: Vessel count and expression of VEGF may be useful for predicting distant recurrence in patients with node-negative colon cancer.     

Pharmacokinetics of tacrolimus (FK506) in primary orthotopic heart transplant patients

STUDY OBJECTIVES: Local recurrence is high when sublobar resection is chosen as primary management of stage I non-small cell lung carcinoma. Postoperative external-beam radiotherapy may reduce this local recurrence problem. A technique of intraoperative brachyradiotherapy following thoracoscopic wedge resection is described as an alternative to adjuvant external-beam radiotherapy for high-risk patients who are not candidates for pulmonary lobectomy. PATIENTS: Fourteen patients with significant impairment in cardiopulmonary function having small peripheral solitary pulmonary nodules underwent video-assisted thoracoscopic (VATS) wedge resection and were found to have non-small cell cancer. Surgical margins were pathologically clear and mediastinal nodes were benign-stage I (T1NO). INTERVENTIONS: A custom polyglyconate mesh (Vicryl) containing 125I seeds was applied to pulmonary resection margins following wedge resection of peripheral lung cancers. A total dose of 100 to 120 Gy at 1 cm was applied to the target area. RESULTS: All patients had histologically clear surgical margins. Postoperative dosimetry confirmed adequate resection margin coverage. There was neither operative mortality nor morbidity related to the VATS wedge resection or the brachytherapy implants. Implants did not migrate, and there were no cases of significant radiation pneumonitis or local recurrence at mean follow-up of 7 months (range, 2 to 12 months). CONCLUSIONS: Intraoperative brachytherapy appears to be a safe and efficient alternative to external-beam radiation therapy when adjuvant radiotherapy is considered following therapeutic wedge resection of stage I (T1NO) lung cancers. The impact on local recurrence, disease-free interval, and survival will require additional follow-up.     

Effectiveness of postoperative irradiation in stage IIIA non-small cell lung cancer according to regression tree analyses of recurrence risks

BACKGROUND: In the setting of grossly resected stage IIIA (N2 involvement) non-small cell lung carcinoma, the role of adjuvant postoperative thoracic radiation therapy (TRT) remains controversial. This study was initiated to subcategorize these patients into high-, intermediate-, and low-risk groups with respect to local recurrence and survival rates, and to determine whether there were certain subgroups of patients who were particularly likely or unlikely to benefit from postoperative TRT. METHODS: Two hundred twenty-four patients were studied. A regression tree analysis was used to separate patients who had undergone operation alone into groups that had a high, intermediate, or low risk of local recurrence and death. The effect of adjuvant postoperative TRT then was examined in each of these groups. RESULTS: The use of adjuvant postoperative TRT (compared with operation alone) was associated with an improvement in freedom from local recurrence and survival for patients who had an intermediate or high risk of local recurrence and death. However, the greatest level of improvement in freedom from local recurrence (p < 0.0001) and survival (p = 0.0002) associated with the use of adjuvant postoperative TRT was in the high-risk group. Similarly, but of lesser magnitude, the intermediate-risk group had improved freedom from local recurrence and survival rates with the use of adjuvant post-operative TRT (p = 0.002 and p = 0.01, respectively). For the low-risk group, the freedom from local recurrence and survival rates were not statistically different between the patients who received adjuvant postoperative TRT and those who underwent observation. CONCLUSIONS: Patients with non-small cell lung carcinoma involving ipsilateral mediastinal lymph nodes (stage IIIA) who undergo gross resection and who are at either high or intermediate risk for local recurrence and death are likely to benefit from adjuvant postoperative irradiation. The role of radiation therapy in low-risk patients is unclear. Prospective confirmation of these observations is warranted.     

Retinoblastoma protein expression in lung cancer: an immunohistochemical analysis

Several analyses of the retinoblastoma (RB) gene in lung cancer at the DNA, mRNA and protein levels have recently been reported. In particular, small cell lung carcinoma shows a high incidence of RB gene abnormalities, suggesting that alterations of this gene may participate in tumor development. In the present study, we used an immunohistochemical technique with a monoclonal antibody raised against RB protein (PMG3-245) to detect its expression in representative paraffin sections of tissues obtained from 108 patients with various types of lung cancer treated by surgical resection of the primary tumor. While deletion of RB protein expression was observed in 7 (88%) of small cell lung carcinomas, only 17 (17%) of 100 non-small cell lung carcinomas showed decreased RB protein levels and 6 (6%) showed no RB protein expression. This low incidence of RB protein expression abnormalities in non-small cell lung carcinomas was significant (p < 0.0001). Thus, in contrast to small cell lung carcinoma, abnormalities in RB protein expression may be minor events in non-small cell lung carcinoma. In addition, no significant correlation was found between abnormalities in RB protein expression and clinical factors such as stage, tumor size, and nodal involvement in non-small cell lung carcinoma. However, abnormalities in RB protein expression in squamous cell carcinoma were observed only in the less differentiated types (p = 0.144), and there was a weak but not statistically significant association in non-small cell lung carcinoma between RB protein status and prognosis (p = 0.09). Therefore, in non-small cell lung carcinoma, although abnormalities in RB protein appear not to be closely associated with tumor development, further studies on a larger scale and with a longer-term follow-up are required to determine the clinicopathological significance of RB gene abnormalities, in particular the relationship between abnormalities of RB protein and differentiation or prognosis.     

Programming of enzyme specificity by substrate mimetics: investigations on the Glu-specific V8 protease reveals a novel general principle of biocatalysis

BACKGROUND: The purpose of the study was to determine the accuracy and role of the sentinel node technique in patients with non-small cell lung cancer. METHODS: This study was carried out on 36 consecutive patients undergoing lung resection. Peritumoral tissue was infiltrated with isosulfan blue dye and the first lymph node to stain was identified as a sentinel node. Sensitivity and specificity of the sentinel node in predicting the status of other lymph node stations were determined. RESULTS: Seventeen patients had sentinel lymph nodes. In 9 of these 17 cases neither the sentinel node nor any other lymph node contained metastatic carcinoma. In 5 cases the sentinel node was in the mediastinum and documented unexpected N2 disease. In 19 patients no sentinel node was found. Final lymph node statuses were N0 in 13 patients, N1 in 5, and N2 in 1. CONCLUSIONS: The use of isosulfan blue for intraoperative lymphatic mapping is feasible. The specificity in our experience was good; 9 of 9 patients with negative sentinel nodes were found to be N0 on the final pathology report. Unexpected N2 disease was found in 5 patients. The accumulation of further experience will determine the role of the sentinel node technique in patients with non-small cell lung cancer.     

Incidence of iron-deficiency anaemia and depleted iron stores among nine-month-old infants in Vancouver, Canada

The authors analysed a group of 80 patients who were operated in 1985-1990 on account of non-small cell carcinoma of the lungs in stage IIIA with affection of the ipsilateral mediastinal nodes. The patients were not treated by neoadjuvant chemotherapy and systematic dissection of the mediastinal nodes was not performed. The results of five-year survival in the group of patients with affection of the mediastinal nodes (N2) were compared with those in the group of patients without affection of the mediastinal and hilar nodes (NO). Patients with affected N2 nodes who survived five years were significantly fewer than patients with negative mediastinal and hilar nodes. The probability of five-year survival in N2 was 15.8%, in patients with NO 28.0%. From data in the literature it is known that neoadjuvant chemotherapy and subsequent complete resection of the lung with the tumour combined with dissection of the mediastinal nodes may improve long-term survival after surgery. The authors assume that introduction of the described methods in their department will improve postoperative results.     

Analysis of cancer modality and distribution in China from year 1990 through 1992--an epidemiologic study

OBJECTIVE: Bronchopulmonary carcinosarcoma is a very rare tumor and the prognosis of patients with carcinosarcoma is assessed as unfavourable. The problems concerning diagnosis, therapy, and prognosis after resection treatment are discussed with reference to our seven cases and with consideration of the pertinent literature. METHODS: The retrospective data of seven patients with pulmonary carcinosarcoma were analysed. All were staged postoperatively according to the international TNM staging system. The diagnosis was verified by immunohistochemical investigation. The prognosis of the patients with carcinosarcoma was compared with the prognosis of patients with non-small cell carcinoma of the lung. RESULTS: Whether lung resection is the treatment of choice for these patients is of no relevance, because in most cases the preoperative diagnosis is incomplete, as only one component of the tumor, namely the epithelial one, is found in the biopsy specimen. The complete and correct diagnosis in five of the seven cases was not made before the resection had been performed and in the remaining two patients it was only made when tumor recurrence or metastases occurred. The prognosis of patients with carcinosarcoma of the lung is assessed to be comparable to that of patients with other pulmonary carcinoma: in this study survival times ranged from only 3 months (T2N3) to 4 years 6 months (T3N1). The causes of death of the patients with carcinosarcoma were local recurrence in four patients and metastases at distant sites in two. Two recurrent tumors as well as the metastases consisted only of the sarcoma component of the primary tumor histologically. CONCLUSION: One may suggest that the prognosis of carcinosarcoma might be determined by the sarcoma component of the tumor. Therefore the generally accepted therapies of soft tissue sarcomas should be adopted for the follow-up treatment of patients with pulmonary carcinosarcoma.     

Prognostic value of immunohistochemically identifiable tumor cells in lymph nodes of patients with completely resected esophageal cancer

BACKGROUND: Current methods of disease staging often fail to detect small numbers of tumor cells in lymph nodes. Metastatic relapse may arise from these few cells. METHODS: We studied 1308 lymph nodes from 68 patients with esophageal cancer without overt metastases who had undergone radical en bloc esophagectomy. A total of 399 lymph nodes obtained from 68 patients were found to be free of tumor by routine histopathological analysis and were studied further for isolated tumor cells by immunohistochemical analysis with the monoclonal anti-epithelial-cell antibody Ber-EP4. This antibody did not stain lymph nodes from 24 control patients without carcinoma. RESULTS: Of the 399 "tumor free" lymph nodes, 67 (17 percent), obtained from 42 of the 68 patients, contained Ber-EP4-positive tumor cells. Fifteen of 30 patients who were considered free of lymph-node metastases by histopathological analysis had such cells in their lymph nodes, and 5 of the 15 had small primary tumors. Ber-EP4-positive cells found in "tumor free" nodes were independently predictive of significantly reduced relapse-free survival (P=0.008) and overall survival (P=0.03). They predicted relapse both in patients without nodal metastases (P=0.01) and in those with regional lymph-node involvement (P=0.007). All 12 patients whose lymph nodes were negative on both histopathological and immunohistochemical analysis and who were available for follow-up survived without recurrence. The presence of micrometastatic tumor cells in bone marrow had no additional prognostic value. CONCLUSIONS: Immunohistochemical examination of lymph nodes may improve the pathological staging of esophageal cancer.     

Fibrolamellar carcinoma of the liver: composition of the extracellular matrix and expression of cell-matrix and cell-cell adhesion molecules

We have analyzed the composition of the tumor stroma and the expression of cell-matrix and cell-cell adhesion molecules in 11 cases of fibrolamellar carcinoma of the liver (FLC), in comparison with 34 cases of hepatocellular carcinoma and 8 cases of focal nodular hyperplasia. Fibrolamellar carcinoma was characterized by the presence of large amounts of tenascin in tumor stroma and by the scarce expression of basement membrane components at the contact of neoplastic clusters. Like normal hepatocytes, neoplastic cells constantly expressed the alpha1 integrin chain, lacked the beta4 integrin chain, and coexpressed E-cadherin and the hepatocyte N-related cadherin. Abnormalities in the expression of cell adhesion molecules, including altered cadherin expression, alphaV integrin chain induction, and CD44 expression, were detected in the majority of cases. The composition of the tumor stroma and the pattern of expression of cell adhesion molecules in fibrolamellar carcinoma were reminiscent of those observed in grade III and grade IV hepatocellular carcinomas. Our results therefore show that, despite its slow local growth and good prognosis, fibrolamellar carcinoma expresses many characteristics usually associated with clinically aggressive malignancies. Further studies are needed to identify the factors responsible for the apparent dissociation between clinical behavior and biological characteristics in this tumor.     

Successful treatment of solitary extracranial metastases from non-small cell lung cancer

BACKGROUND: Recurrence after resection of non-small cell lung carcinoma is generally associated with a poor outcome and is treated with either systemic agents or palliative irradiation. Recently, long-term survival has been reported after resection of isolated brain metastases from non-small cell lung carcinoma, but resection of other metastatic sites has not been explored fully. METHODS: We have identified 14 patients who had solitary extracranial metastases treated aggressively after curative treatment of their non-small cell lung carcinoma. The histology was squamous carcinoma in 5, adenocarcinoma in 8, and large cell carcinoma in 1. Initially, 3 patients had stage I, 5 stage II, and 6 stage IIIa disease. RESULTS: The sites of metastases included extrathoracic lymph nodes (six), skeletal muscle (four), bone (three), and small bowel (one). The median disease-free interval before metastases was 19.5 months (range, 5 to 71 months). Complete surgical resection of the metastatic site was the treatment in 12 of 14 patients. Two patients received only curative irradiation to the metastatic site, with complete response. The overall 10-year actuarial survival (Kaplan-Meier) was 86%. To date, 11 patients are alive and well after treatment of their metastases (17 months to 13 years), 1 has recurrent disease, 1 died of recurrent widespread metastases, and 2 died of unrelated causes. CONCLUSION: Long-term survival is possible after treatment of isolated metastases to various sites from non-small cell lung carcinoma, but patient selection is critical.     

Value of postoperative radiotherapy in malignant tumors of the upper urinary tract. Apropos of a series of 26 patients

To evaluate the role of adjuvant radiation therapy in invasive transitional cell carcinoma of the upper urinary tract, we retrospectively reviewed a series of 26 patients who underwent radical surgery plus post-operative prophylactic irradiation for such a tumor. Between 1980 and October 1993, 18 men and eight women (mean age: 65 +/- 9 years) were treated for an invasive transitional cell carcinoma of the upper urinary tract. Tumor location was the renal pelvis in 15 patients (58%). The tumor was pathological stage B in 11 patients (42%) and stage C in 15 patients (58%). Tumor grade was 2 in ten patients, 3 in 15 and unknown in one. Nine patients had node involvement. All patients underwent surgery followed by radiation therapy to a total dose of 45 Gy to the tumor bed (23 patients) and/or regional nodes (18 patients). After a mean follow-up of 45 months, 13 patients (50%) were alive and 11 were disease-free. Local tumor relapse, nodal recurrence, metastasis and second urothelial location were noted in one, four (15%), 14 (54%) and eight patients (30%) respectively. Overall 5-year survival and 5-year disease-free survival were 49% and 30% respectively. Overall 5-year survival rates were 60% for stage B and 19% for stage C disease (P = 0.07), 43% for node-negative versus 15% for node-positive cancer (P = 0.04) and 90% for grade 2 and 0% for grade 3 tumors (P < 0.01). In this study using a radio-surgical approach, local control of disease and survival were similar to those reported previously in surgical series. Prophylactic post-operative radiation therapy is not recommended.     

Axillary lymph node metastases from bronchogenic carcinoma

BACKGROUND: Axillary lymph node metastases (ALNMs) from bronchogenic carcinoma are rare and their significance may be questioned. A surgical approach may allow a better understanding of the mechanism of their occurrence. METHODS: A retrospective study of 1,486 cases of surgically removed non-small cell lung carcinoma was performed. Twenty-two patients (1.5%) had extrathoracic nodal metastases. Nine of them were ALNMs (<1%). These cases form the basis of this study. RESULTS: In 1 patient ipsilateral ALNM was removed during a lung operation. It was a left non-small cell lung carcinoma invading the chest wall (T3 N2). In the other patients (n = 8) ALNMs were observed during postoperative follow-up; 4 underwent ALNM resection, 2 had radiotherapy, and 2 had symptomatic treatment only. For these 8 patients, in the TNM classification performed after an initial bronchogenic carcinoma operation, the lymph node status was, respectively, N0 in four cases, N1 in three cases, and N2 in one case. Survival ranged from 1 to 10 months, except for one patient who is still alive after more than 5 years. In this case, the ALNM was discovered 4 months after a right lower lobectomy for a T2 N0 adenocarcinoma. CONCLUSIONS: Axillary lymph node metastases may be involved through direct chest wall invasion of bronchogenic carcinoma or retrograde spread from supraclavicular lymphnode block. However, another mechanism seems to be the systemic vascular route.     

Neuronal expression of Fos and Jun protein in the rat medulla and spinal cord after anoxic and hypercapnic stimulations

The levels of the new tumour marker CYFRA 21-1 were assessed in 115 patients with non-small cell lung cancer (NSCLC) and in 45 patients with non-malignant lung disease. Increased levels of CYFRA 21-1 were observed in 47.8%, mostly in patients with squamous cell carcinoma (SCC; 69.1%). Serum CYFRA 21-1 levels were correlated with the stage of SCC type. Positive CYFRA 21-1 levels in patients with SCC were present in 40% of stage I, 61.1% of stage II, and 85.2% of stage III. In addition, SCC patients who presented mediastinal lymph nodes (N2) demonstrated higher serum CYFRA 21-1 levels, compared with patients without mediastinal lymph nodes metastases (N0 or N1). With regard to tumour size, significant difference was observed between T1, T2 and T3. The study also showed that the percentage of patients who survived 18 months with normal preoperative level of CYFRA 21-1 was higher compared with those patients with elevated preoperative levels of this marker, but the differences were not statistically significant.     

The possible significance of parallel changes in plasma lutein and retinol in Pakistani infants during the summer season

We established new cell lines from head and neck cancer patients for studies of adhesion molecules and cellular behavior in nine patients with primary or metastatic cancer treated at the Asan Medical Center. Explant cultures of fresh tumor tissue were used to develop new permanent tumor cell lines. Lines were tested for tumor formation and histology in nude mice. Flow cytometry and indirect immunofluorescence were used to assess DNA content and expression of the alpha 6, beta 4, and beta 1 integrin subunits and the intercellular adhesion molecule 1 (ICAM-1). In vitro growth patterns and adhesion to plastic were assessed using phase contrast microscopy. AMC-HN-1 to -8 were derived from patients with squamous cell carcinoma. AMC-HN-9 was from an undifferentiated carcinoma of the parotid gland. The 8 lines we tested produced nude mouse tumors that are identical to the histology of the original tumors. AMC-HN-1, -2, -5, and -9 have epithelioid or spindle cell morphology with poor cell-to-cell and cell-to-substrate adhesiveness. AMC-HN-3, -4, -7, and -8 grow as adherent epithelioid monolayers. AMC-HN-6 exhibits multilayer stratification. Four lines are near diploid, 4 are hyperdiploid and 1 is hypodiploid. Only three express ICAM-1. All lines express the alpha 6, beta 4, and beta 1 integrin subunits but to different extent. Four, AMC-HN-1, -2, -5, and -6, express the beta 4 integrin at low levels, AMC-HN-3, -4, -7, and -9, have intermediate beta 4 expression, and AMC-HN-8 has extremely high beta 4 expression. The AMC-HN cell lines are representative in vitro models for the study of head and neck cancer biology. Our preliminary results indicate a close relationship between integrin expression and cell adhesion in vitro.     

Does wild-type p53 play a role in normal cell differentiation?

The integrin family consists of broadly expressed cell surface adhesion receptors, each member of which is composed of a non-covalently linked alpha/beta heterodimer. Integrin receptors are involved in the interaction with matrix proteins and may contribute to invasion and metastasis of carcinomas. To examine the biological role integrins play in colorectal carcinoma we compared the expression of integrin alpha- and beta-subunits in situ and in vitro. Eight newly established cell lines derived from immunohistochemically characterized colorectal carcinomas together with two sublines obtained after nude mouse passage and the commonly used colon carcinoma lines HT-29, SW480, SW620, and COLO 205 were investigated by immunocytochemistry and flow cytometry. The carcinomas in situ expressed alpha 1-, alpha 2-, alpha 3-, alpha 6-, alpha v- and beta 1-subunits in variable amounts while being devoid of alpha 4, alpha 5, and beta 3. The individual integrin profile of the tumour in tissue was essentially maintained in vitro. However, a neo expression of the alpha 5 chain was found, together with an induction or increase in alpha 1, alpha 2, alpha 3, alpha v and beta 1 levels. No decrease in integrin subunit expression was observed. Standard-serum and serum-free medium revealed no striking differences in alpha- and beta-chain expression in the cell lines HT-29 and COLO 205. In serum-free medium, SW480 showed a slight increase of alpha 1 and alpha 5 and a decrease of alpha 3 and alpha v while SW620 expressed more alpha 1. We conclude that the great variability of adhesion receptor expression of the integrin family in colorectal carcinomas in situ is essentially maintained in vitro, although culture conditions which are only marginally influenced by serum factors unpredictably lead to some increase in expression or even induction of several integrin subunits.     

Prognostic significance of HER-2/neu overexpression in stage I adenocarcinoma of lung

BACKGROUND: Even with early diagnosis and adequate resection, the 5-year survival rate for stage I lung cancer patients is around 60% to 70%. Overexpression of HER-2/neu protein is associated with poor prognosis in lung cancers. In this study, we evaluated the expression of HER-2/neu in cancer cells of lung and assessed their clinicopathologic and prognostic significance. METHODS: From 1986 to 1995, clinical data on 42 consecutive patients who underwent complete surgical resection for stage I lung adenocarcinoma were collected. Expression of HER-2/neu in paraffin-embedded tumor samples was determined by immunohistochemistry and scored with a semiquantitative method. RESULTS: Twenty-one of 42 patients were positive for HER-2/neu overexpression in tumor. Compared with patients with low HER-2/neu expression, patients with HER-2/neu overexpression had a significantly higher incidence of early tumor recurrence (p = 0.014). Survival was also significantly better in patients without HER-2/neu overexpression than in those with HER-2/neu overexpression (p = 0.0047). By univariate analysis, HER-2/neu overexpression and poor cell differentiation are two important factors correlated with poor prognosis. CONCLUSIONS: Expression of HER-2/neu oncoprotein in stage I lung adenocarcinoma can predict the tumor's aggressiveness. Early tumor recurrence was frequently detected in patients with HER-2/neu overexpression. We recommend an individualized therapeutic strategy based on the level of HER-2/neu oncoprotein in the tumor cells.     

Biochemical characterization of human osteoclast integrins. Osteoclasts express alpha v beta 3, alpha 2 beta 1, and alpha v beta 1 integrins

The study of osteoclast integrins has been previously hampered by the lack of a source of large numbers of purified osteoclasts. Osteoclastoma, a human giant cell tumor of bone, supplied a rich source of osteoclasts within a tissue containing many diverse cell types. Osteoclastoma integrin immunostaining confirmed the presence of the integrin alpha v beta 3 complex and the alpha 2 and beta 1 integrin subunits on osteoclasts. However, weak integrin expression, for example with alpha v beta 5, was difficult to interpret. Purification with magnetic beads coated with vitronectin receptor monoclonal antibody (13C2) enabled osteoclast membranes to be isolated with high purity and yield (57%) from osteoclastoma tissue. Positively (osteoclast-enriched) selected membranes were biochemically assessed for integrin expression by immunoprecipitation and visualization by non-radioactive enhanced chemiluminescence. alpha 1, alpha 4, alpha 6, alpha 8, alpha M, alpha X, gpIIb, beta 4, beta 6, and beta 8 integrin chains were undetectable at a sensitivity of 1 ng. alpha 3, alpha 5, alpha L, beta 2, and alpha v beta 5 were found in the negatively selected osteoclastoma tissue but not in the positively purified osteoclast membranes. The presence of alpha v beta 1 and alpha 2 beta 1 dimers was demonstrated biochemically on the immunoisolated osteoclast membranes. Osteoclast alpha v beta 3 isolation by Arg-Gly-Asp (RGD) affinity chromatography for NH2-terminal amino acid sequencing confirmed that the osteoclast vitronectin receptor was identical to that previously characterized on other cell types. In situ hybridization using human alpha v riboprobes in osteoclasts from human and rodent bone further demonstrated the high level and specificity of expression of alpha v vitronectin receptor in osteoclasts.